Whitening Agent And Skin External Preparation

ABSTRACT

The present invention provides a compound having an excellent inhibitory action on melanin production and being useful as a whitening agent, and a skin external preparation containing the compound. The whitening agent of the present invention comprises, as an active ingredient, a heterocyclic compound represented by formula (1) or a pharmacologically acceptable salt thereof: 
     
       
         
         
             
             
         
       
     
     wherein R 1 , R 2 , and R 2 ′ are each independently C 1-3  alkyl; Y is S or O; and p is an integer of 0 to 3, wherein when p is 2 or 3, R 1  may be the same or different.

RELATED APPLICATIONS

This application claims the priority of Japanese Patent Application No. 2008-29106 filed on Feb. 8, 2008 and Japanese Patent Application No. 2008-199606 filed on Aug. 1, 2008, which are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to a whitening agent and a skin external preparation, and particularly, to an active ingredient thereof.

BACKGROUND OF THE INVENTION

Pigmentation in the skin such as pigmented spots and freckles are resulted from hyperpigmentation of melanin in the epidermis. The hyperpigmentation is caused by acceleration of melanin production in epidermal melanocytes triggered by hormone abnormality or UV stimulation.

A whitening agent has been mixed into a skin external preparation with an aim to prevent and improve such abnormal melanin pigmentation. At present, as ingredients that are mixed into a skin external preparation as a whitening agent, there are vitamin C derivative, kojic acid, arbutin (4-hydroxyphenyl-β-D-glucopyranoside), Rucinol (4-n-butylresorcinol), ellagic acid, etc, which are known to have an inhibitory action on melanin production.

However, a whitening agent fully satisfactory in terms of the effect, safety, and the like has not yet been obtained, and therefore development of a new whitening agent has been demanded.

On the other hand, Patent Literature 1 describes a thiazoline compound having a pest control effect on a harmful organism.

However, this literature is totally silent on an inhibitory action on melanin production and a whitening effect.

Patent Literature 1: Japanese Unexamined Patent Publication No. H6-25197

DISCLOSURE OF THE INVENTION Problem to be Solved by the Invention

The present invention has been accomplished in view of the aforementioned problem of the conventional art. An object of the present invention is to provide a compound having an excellent inhibitory action on melanin production and being useful as a whitening agent, and a skin external preparation containing the compound.

Means to Solve the Problem

The present inventors conducted thorough research to solve the aforementioned problem. As a result, they have found that a specific thiazoline or oxazoline compound has an excellent inhibitory action on melanin production and also has extremely low cytotoxicity, thereby completing the present invention.

That is, the whitening agent of the present invention comprises, as an active ingredient, a heterocyclic compound represented by the following formula (1) or a pharmacologically acceptable salt thereof:

wherein

R₁, R₂, and R₂′ are each independently C₁₋₃ alkyl;

Y is S or O; and

p is an integer of 0 to 3, wherein when p is 2 to 3, R₁ may be the same or different.

The present invention also provides the aforementioned whitening agent, wherein Y is S.

The present invention also provides the whitening agent, wherein R₂ and R₂′ are methyl.

The present invention also provides the whitening agent, wherein p is 1 or 2.

The present invention also provides the whitening agent, wherein R₁ is substituted at the ortho position and/or the para position of the —NH— group.

The present invention also provides the whitening agent, wherein the active ingredient inhibits melanin production.

The present invention also provides a skin external preparation and a cosmetic comprising any of the aforementioned heterocyclic compounds or a pharmacologically acceptable salt thereof.

EFFECT OF THE INVENTION

The whitening agent of the present invention has an excellent inhibitory action on melanin production and also has extremely low cytotoxicity; therefore, it can be suitably mixed into a skin external preparation as a whitening agent.

BEST MODE FOR CARRYING OUT THE INVENTION

The whitening agent of the present invention is represented by the following formula (1):

In the formula (1), R₁, R₂, and R₂′ are each independently C₁₋₃ alkyl.

In the present invention, the “C₁₋₃ alkyl” is a linear, branched, or cyclic saturated hydrocarbon group having from 1 to 3 carbon atoms. Examples thereof include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, and a cyclopropyl group. Preferred alkyl includes methyl and ethyl, and particularly preferred alkyl is methyl.

Y is S or O. Thus, in the formula (1), the 5-membered hetero ring containing Y is thiazoline (in the case where Y═S) or oxazoline (in the case where Y═O).

p is an integer of 0 to 3. When p is 2 to 3, R₁ may be the same or different.

An example of the preferred compound as an active ingredient of the whitening agent of the present invention is the compounds wherein Y is S.

Another example of the preferred compound as an active ingredient of the whitening agent of the present invention is the compounds wherein R₂ and R₂ are methyl.

Another example of the preferred compound as an active ingredient of the whitening agent of the present invention is the compounds wherein p is 1 or 2.

Another example of the preferred compound as an active ingredient of the whitening agent of the present invention is the compounds wherein R₁ is substituted at the ortho position and/or the para position of the —NH— group.

It is to be noted that the compounds of the formula (1) can be tautomers as shown below. In the present invention, such tautomers are also included in the compounds of the formula (1).

The compound of the formula (1) can be synthesized by a known method or commercially available.

In the case of synthesis, when the molecule has a functional group which blocks or might block a reaction, an appropriate protecting group is preferably used to allow the reaction to proceed efficiently. The use of the protecting group can be carried out according to, for example, Protective Groups in Organic Synthesis by Theodora W. Greene and Peter G. M. Wuts. Further, when an isomer such as a conformational isomer, a geometric isomer, and an optical isomer is present, a pure isomer or geometric isomer can be obtained by appropriately selecting a raw material and a reaction condition and performing a separation operation. In the present invention, a pure isomer of the compound of the formula (1) as well as a mixture thereof are also included.

A compound of the formula (1) can be obtained by, for example, a reaction shown in the following scheme 1.

In scheme 1, a reaction, of an iso(thio)cyanate compound (2) with an ethanolamine compound (3) can be carried out, for example, in an appropriate solvent such as chloroform, while heating as needed. A ring closure reaction of the (thio)urea compound (4) thus obtained can be carried out, for example, in the presence of an acid catalyst, while heating. This reaction can be carried out according to, for example, a method described in Japanese Unexamined Patent Publication No. S62-228089.

Alternatively, as a method described in Japanese Unexamined Patent Publication No. 6-25197, a reaction of 2-imino (or 2-amino) thiazoline compound (or oxazoline compound) with a compound represented by (R₁)p-C₆H₄—X (wherein X is a halogen; and R₁ and p are each independently as defined above) can also be adopted. This reaction can typically be carried out in an appropriate solvent in the presence of a base such as triethylamine, while heating as needed.

The compound of the formula (1) can be converted into an acid-addition salt by an ordinary method as needed. Examples of acid in the acid-addition salt include an inorganic salt such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, and an organic acid such as acetic acid, propionic acid, citric acid, lactic acid, oxalic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, and methanesulfonic acid.

The compound of the formula (1) has an excellent inhibitory action on melanin production while exhibiting extremely low cytotoxicity. Therefore, the present compound is useful as a whitening agent and can be suitably mixed into various skin external preparations, particularly a skin external preparation intended to improve or prevent pigmented spots, freckles, skin dullness, and the like.

When the compound of the formula (1) is mixed into the skin external preparation as the whitening agent, the compound amount is, in the total amount of the external agent, typically 0.0002% by mass or more, preferably 0.002% by mass or more. When it is too low, the effect cannot be fully exerted. Although no limitation is imposed on the upper limit, it is typically 30% by mass or less, preferably 20% by mass or less, and more preferably 5% by mass or less. When the compound is excessively mixed in, not only a remarkable effect reasonably expected from the increased amount may not be obtained but also formulation designing and usability may be affected.

Other than adding the compound of the formula (1), the skin external preparation of the present invention can be produced by an ordinary method.

In addition to the compound of the formula (1), other ingredients normally used in a skin external preparation such as a cosmetic product and a pharmaceutical product can be appropriately added to the skin external preparation of the present invention as needed as far as the effect of the present invention is not adversely affected. Examples of such an ingredient include oil, a humectant, an ultraviolet protective agent, an antioxidant, a metal ion chelating agent, a surfactant, a preservative, a moisturizer, a fragrance, water, an alcohol, a thickener, powder, a colorant, a crude drug, and various kinds of medicinal ingredients.

Further, other whitening agents such as vitamin C, magnesium ascorbyl phosphate, ascorbyl glucoside, arbutin, kojic acid, Rucinol, ellagic acid, tranexamic acid, and linoleic acid can be appropriately added.

The skin external preparation of the present invention is widely applicable to the fields of cosmetics, drugs, and quasi drugs. No particular limitation is imposed on the form of the skin external preparation as long as it is applicable to the skin. Any form such as a solution, an emulsion, a solid, a semi-solid, a powder, a powder dispersion, a water-oil-separated two-phase liquid, a water-oil-powder-separated three-phase liquid, an ointment, a gel, an aerosol, a mousse, and a stick can be applied. Further, the skin external preparation can be provided in any use form including a facial cosmetic such as a lotion, an emulsion, a cream, a pack, an essence, and a gel, and a makeup cosmetic such as a foundation, a makeup base, and & concealer.

Hereinbelow, the present invention will be further described with specific examples. However, the present invention is not limited thereto.

EXAMPLES

A test for melanin production inhibition by the compounds of the formula (1) was conducted. The test method is as follows.

Melanin Production Inhibition Test

(1) Inoculation of Cells and Addition of Test Substances

Mouse B16 melanoma cells were inoculated in a six well plate at 100,000 cells/well. The next day, test substance solutions (solvent: DMSO) were added.

(2) Cell Proliferation Test

Three days after the addition of the test substance solution, the medium was removed by aspiration. Then 1 ml of EMEM medium containing 10% Alamar Blue solution was added, and a reaction was allowed to proceed at 37° C. After 30 minutes, 100 μL of the reaction mixture was transferred to a 96 well plate and fluorescence was measured at an excitation wavelength of 544 nm and a measurement wavelength of 590 nm. Using the value thus measured as a relative value of cell count, a ratio of the cell count (% cell count) of the test substance-added group to the test substance-absent group (group in which only the solvent was added) was calculated. The higher the % cell count, the lower the cytotoxicity. It was determined that a compound having the % cell count of 80% or more was non-cytotoxic, and that a compound having the % cell count of less than 80% was cytotoxic.

(3) Quantification of Melanin

The cells after the cell proliferation test were washed with PBS three times, and then lysed by addition of 200 μl, of 1M NaOH to measure an absorbance at 475 nm. Using the value thus measured as a relative value of the melanin amount, a ratio of the melanin amount (%) of the test substance-added group to the test substance-absent group (group in which only the solvent was added) was calculated. The lower the ratio of the melanin amount, the higher the melanin production-inhibitory effect. In the final concentrations of the test substances at which the compound was determined to be non-cytotoxic, the minimum final concentration of the test substance at which the ratio of the melanin amount (%) was 80% or less was provided as a minimum concentration for inhibition of melanin production (ppm). The inhibitory effect on melanin production was evaluated according to the following criteria.

-   -   ⊚: the minimum concentration for inhibition of melanin         production was 1 ppm or less.     -   ◯: the minimum concentration for inhibition of melanin         production was more than 1 ppm and 10 ppm or less.     -   X: no inhibitory effect on, melanin production was exhibited at         10 ppm or less (the ratio of the melanin amount was not 80% or         less even at 10 ppm or less).

The results of melanin production inhibition test using the compounds of the present invention are shown in Table 1.

Any of the compounds shown in Table 1 was acknowledged to have an inhibitory effect on melanin production, and most of them exhibited the effect at such an extremely low concentration as 1 ppm or less.

TABLE 1

Inhibitory effect on melanin No. Y R₂ R₂′ R_(1a) R_(1b) R_(1c) R_(1d) R_(1e) production 1 S Me Me H H H H H ⊚ 2# S Me Me H H H H H ⊚ 3 S Me Me Me H Me H H ⊚ 4 S Me Me Me H H H H ○ 5 S Me Me H H Me H H ⊚ 6 S Me Me Me H H H Me ⊚ 7 O Me Me H H H H H ⊚ #: HCL salt, Me: Methyl

Hereinbelow, representative synthesis examples of the heterocyclic compounds used for the whitening agent of the present invention will be shown. Various heterocyclic compounds can be obtained by carrying out a reaction according to the below-described synthesis examples using a corresponding raw material.

Synthesis Example 1 Synthesis of 4,4-dimethyl-N-phenyl-4,5-dihydrothiazol-2-amine (Compound 1)

In 500 g of chloroform was dissolved 2-amino-2-methyl-1-propanol (61.6 g, 0.69 moL). Then, 300 g of chloroform solution containing phenyl isothiocyanate (81.6 g, 0.6 moL) was slowly added dropwise to the mixture over one hour, while stirring. Upon completion of the addition, the resulting mixture was stirred for 12 hours at room temperature. The precipitated crystals were refluxed with heat to be dissolved and then recrystallized. The crystals thus obtained were collected by filtration, washed with 20 mL of diethyl ether three times, and then dried under reduced pressure at room temperature to give 80.1 g of N-(1-hydroxy-2-methylpropan-2-yl)-N-phenylthiourea (yield 60%).

N-(1-hydroxy-2-methylpropan-2-yl)-N-phenylthiourea (80.1 g, 0.36 mol) was dissolved in 2,400 mL of 35% HCl, and the resulting mixture was stirred while heating at 90° C. for 1.5 hours. After cooling, the mixture was neutralized with NaOH and extracted with diethyl ether. The extract was washed with saturated brine and then anhydrous sodium sulfate was added. The organic phase was distilled off under reduced pressure and the residue was washed three times with hexane. The crystals thus obtained were dried under reduced pressure at room temperature, and then recrystallized from methanol twice to give 22.4 g of the title compound (yield 18%).

¹H-NMR(CDCl₃): 1.39 (61H, s), 3.08 (2H, s), 7.01-7.09 (3H, m), 7.26-7.30 (2H, m)

Hereinbelow, Formulation Examples of the skin external preparation of the present invention are shown. In each Formulation Example, one or more compounds of the present invention can be used. Any of the skin external preparations shown in Formulation Examples below exerts a whitening effect because of the by the addition of the compound of the present invention.

Formulation Example 1 Cream (Formulation)

Stearic acid 5.0% by mass Stearyl alcohol 4.0 Isopropyl myristate 18.0 Glyceryl monostearate 3.0 Propylene glycol 10.0 Compound of the present invention 0.1 Caustic potash 0.2 Sodium bisulfite 0.05 Preservative q.s. Fragrance q.s. Ion-exchanged water balance

(Production Method)

Propylene glycol and caustic potash were dissolved in ion-exchanged water, and the resulting mixture was heated to and maintained at 70° C. (aqueous phase). Other components were mixed and melted by heat, and maintained at 70° C. (oil phase). The oil phase was gradually added to the aqueous phase, and after the complication of the addition, the resulting mixture was maintained at 70° C. for some time to allow a reaction to proceed. Subsequently, the mixture was homogeneously emulsified by a homomixer, and cooled to 30° C. while thoroughly stirring.

Formulation Example 2 Cream (Formulation)

Stearic acid 5.0 by mass % Sorbitan monostearate 2.5 Polyoxyethylene (20) sorbitan monostearate 1.5 Arbutin 7.0 Sodium bisulfite 0.03 Propylene glycol 10.0 Compound of the present invention 0.05 Glyceryl trioctanoate 10.0 Squalene 5.0 Octyl p-dimethylaminobenzoate 3.0 Disodium ethylenediaminetetraacetate 0.01 Ethylparaben 0.3 Fragrance q.s. Ion-exchanged water balance

(Production Method)

Propylene glycol and disodium ethylenediaminetetraacetate were dissolved in ion-exchanged water and the resulting mixture was maintained at 70° C. (aqueous phase). Other components were mixed and melted by heat, and maintained at 70° C. (oil phase). The oil phase was gradually added to the aqueous phase. The mixture was preliminarily emulsified at 70° C., homogeneously emulsified by a homomixer, and then cooled to 30° C. while thoroughly stirring.

Formulation Example 3 Cream (Formulation)

Solid paraffin 5.0% by mass Beeswax 10.0 Petrolatum 15.0 Liquid paraffin 41.0 Glyceryl monostearate 2.0 POE (20) sorbitan monolaurate 2.0 Soap powder 0.1 Borax 0.2 Compound of the present invention 0.05 Sodium bisulfite 0.03 Ethylparaben 0.3 Fragrance q.s. Ion-exchanged water balance

(Production Method)

Powder soap and borax were added to ion-exchanged water and dissolved with heat, and the resulting mixture was maintained at 70° C. (aqueous phase). Other components were mixed and melted by heat, and maintained at 70° C. (oil phase). While stirring, the oil phase was gradually added to the aqueous phase to allow a reaction to proceed. Upon completion of the reaction, the mixture was homogeneously emulsified by a homomixer, and then cooled to 30° C. while thoroughly stirring.

Formulation Example 4 Milky Lotion (Formulation)

Stearic acid 2.5% by mass Cetyl alcohol 1.5 Petrolatum 5.0 Liquid paraffin 10.0 POE (10) monooleate 2.0 Polyethylene glycol 1500 3.0 Triethanolamine 1.0 Carboxyvinyl polymer 0.05 Compound of the present invention 0.01 Sodium bisulfite 0.01 Ethylparaben 0.3 Fragrance q.s. Ion-exchanged water balance

(Production Method)

Carboxyvinyl polymer was dissolved in a small amount of ion-exchanged water (phase A). Polyethylene glycol 1500 and triethanolamine were added to the remaining ion-exchanged water and dissolved with heat, and the resulting mixture was maintained at 70° C. (aqueous phase). Other components were mixed and melted by heat, and maintained at 70° C. (oil phase). The oil phase was added to the aqueous phase and preliminarily emulsified. After addition of phase A, the resulting mixture was homogeneously emulsified by a homomixer and then cooled to 30° C. while thoroughly stirring.

Formulation Example 5 Milky Lotion (Formulation)

Microcrystalline wax 1.0% by mass Beeswax 2.0 Lanolin 20.0 Liquid paraffin 10.0 Squalane 5.0 Sorbitan sesquioleate 4.0 POE (20) sorbitan monooleate 1.0 Propylene glycol 7.0 Compound of the present invention 1.0 Sodium bisulfite 0.01 Ethylparaben 0.3 Fragrance q.s. Ion-exchanged water balance

(Production Method)

Propylene glycol was added to ion-exchanged water, and the resulting mixture was heated and maintained at 70° C. (aqueous phase). Other components were mixed and melted by heat, and maintained at 70° C. (oil phase). While stirring the oil phase, the aqueous phase was gradually added to the oil phase. The resulting mixture was homogeneously emulsified by a homomixer and then cooled to 30° C. while thoroughly stirring.

Formulation Example 6 Jelly (Formulation)

95% Ethanol 10.0% by mass Dipropylene glycol 15.0 POE (50) oleyl ether 2.0 Carboxyvinyl polymer 1.0 Caustic soda 0.15 L-arginine 0.1 Compound of the present invention 5.0 Sodium 2-hydroxy-4-methoxybenzophenone sulfonate 0.05 Trisodium ethylenediaminetetraacetate dihydrate 0.05 Methylparaben 0.2 Fragrance q.s. Ion-exchanged water balance

(Production Method)

Carboxyvinyl polymer was homogeneously dissolved in ion-exchanged water. Separately, the compound of the present invention and POE (50) oleyl ether were dissolved in 95% ethanol and then added to the aqueous phase. After addition of the remaining components, the resulting mixture was neutralized by caustic soda and L-arginine to increase the viscosity.

Formulation Example 7 Essence (Formulation) (Phase A)

(Phase A) Ethyl alcohol (95%) 10.0% by mass POE (20) octyldodecanol 1.0 Pantothenyl ethyl ether 0.1 Compound of the present invention 2.0 Methylparaben 0.15 (Phase B) Potassium hydroxide 0.1 (Phase C) Glycerol 5.0 Dipropylene glycol 10.0 Sodium bisulfite 0.03 Carboxyvinyl polymer 0.2 Purified water balance

(Production Method)

Each of Phase A and Phase C was homogeneously dissolved, and Phase A was added to Phase C to be solubilized. After addition of Phase B, the resulting mixture was packed in a container.

Formulation Example 8 Pack (Formulation) (Phase A)

(Phase A) Dipropylene glycol 5.0% by mass POE (60) hydrogenated castor oil 5.0 (Phase B) Compound of the present invention 0.05 Olive oil 5.0 Tocopherol acetate 0.2 Ethylparaben 0.2 Fragrance 0.2 (Phase C) Sodium bisulfite 0.03 Polyvinyl alcohol (saponification degree of 90 13.0 and polymerization degree of 2,000) Ethanol 7.0 Purified water balance

(Production Method)

Each of Phase A, Phase B, and Phase C was homogeneously dissolved, and Phase B was added to Phase A to be solubilized. After addition of Phase C, the resulting mixture was packed in a container.

Formulation Example 9 Solid Foundation (Formulation)

Talc 43.1% by mass Kaolin 15.0 Sericite 10.0 Zinc oxide 7.0 Titanium dioxide 3.8 Yellow iron oxide 2.9 Black iron oxide 0.2 Squalane 8.0 Isostearic acid 4.0 POE sorbitan monooleate 3.0 Isocetyl octanoate 2.0 Compound of the present invention 0.5 Preservative q.s. Fragrance q.s.

(Production Method)

Powdery components from talc to black iron oxide shown above were thoroughly mixed by a blender. To this mixture were added oily components from squalane to isocetyl octanoate shown above, the compound of the present invention, preservative, and fragrance. The resulting mixture was thoroughly kneaded, packed in a container, and then formed.

Formulation Example 10 Emulsion Foundation (Cream-Type) (Formulation) (Powder Part)

(Powder part) Titanium dioxide 10.3% by mass Sericite 5.4 Kaolin 3.0 Yellow iron oxide 0.8 Red iron oxide 0.3 Black iron oxide 0.2 (Oil phase) Decamethylcyclopentasiloxane 11.5 Liquid paraffin 4.5 Polyoxyethylene-modified dimethylpolysiloxane 4.0 Compound of the present invention 0.5 (Aqueous phase) Purified water 50.0 1,3-Butylene glycol 4.5 Sorbitan sesquioleate 3.0 Preservative q.s. Fragrance q.s.

(Production Method)

The aqueous phase was stirred with heat and then the powder part, which had been fully mixed and pulverized, was added. The mixture was treated with a homomixer and then the oil phase, which had been mixed with heat, was added. The mixture was treated with a homomixer and then fragrance was added while stirring. The mixture thus obtained was cooled to room temperature.

Formulation Example 11 Lotion

(1) Compound of the present invention 0.05% by mass (2) Aspartic acid 1.0 (3) Tocopherol acetate 0.01 (4) Glycerol 4.0 (5) 1,3-Butylene glycol 4.0 (6) Ethanol 8.0 (7) POE (60) hydrogenated castor oil 0.5 (8) Methylparaben 0.2 (9) Citric acid 0.05 (10) Sodium citrate 0.1 (11) Fragrance 0.05 (12) Purified water balance

(Production Method)

(2), (4), (5), (9), and (10) were dissolved in (12) to provide a purified water solution. Separately, (1), (3), (7), (8), and (11) were dissolved in (6), and the resulting mixture was added to the aforementioned the purified water solution to be solubilized. The mixture thus obtained was filtrated to provide a lotion.

Formulation Example 12 Lotion

A: Alcohol phase Ethanol 5.0% by mass POE oleyl ether 2.0 2-Ethylhexyl-p-dimethylaminobenzoate 0.18 Compound of the present invention 0.1 Fragrance 0.05 B: Aqueous phase 1,3-Butylene glycol 9.5 2-O-Ethyl ascorbic acid 0.5 Sodium pyrrolidonecarboxylate 0.5 Whey extract 5.0 Nicotinamide 0.3 Glycerol 5.0 Hydroxypropyl-β-cyclodextrin 1.0 Trisodium hydroxyethylethylenediamine triacetate 1.0 Lysine 0.05 Tranexamic acid 1.0 Purified water balance

(Production Method)

Alcohol phase A was added to Aqueous phase B and solubilized to provide a lotion.

Formulation Example 13 Cream (Whitening)

Trans-4-(trans-aminomethylcyclohexanecarbonyl)- 1.0% by mass aminomethylcyclohexanecarboxylic acid hydrochloride Potassium 4-methoxysalicylate 1.0 3-O-Ethylascorbic acid 1.0 Linoleic acid 0.3 Sodium lipoate 1.0 Compound of the present invention 3.0 Coenzyme Q10(CoQ10) 0.03 Petrolatum 2.0 Dimethylpolysiloxane 2.0 Ethanol 5.0 Behenyl alcohol 0.5 Batyl alcohol 0.2 Glycerol 7.0 1,3-Butylene glycol 5.0 Polyethylene glycol 20000 0.5 Jojoba oil 3.0 Squalane 2.0 Phytosteryl hydroxystearate 0.5 Pentaerythritol tetra(2-ethylhexanoate) 1.0 Polyoxyethylene hydrogenated castor oil 1.0 Potassium hydroxide 0.1 Sodium pyrosulfite 0.01 Sodium hexametaphosphate 0.05 Stearyl glycyrrhetinate 0.1 Pantothenyl ethyl ether 0.1 Arbutin 7.0 Tranexamic acid 2.0 Tocopherol acetate 0.1 Sodium hyaluronate 0.05 p-Hydroxybenzoate ester q.s. Trisodium edetate 0.05 4-t-Butyl-4′-methoxydibenzoylmethane 0.1 Glyceryl diparamethoxycinnamate mono-2- 0.1 ethylhexanoate Yellow iron oxide q.s. Xanthan gum 0.1 Carboxyvinyl polymer 0.2 Purified water balance

Formulation Example 14 Two-Phase Cream (Sunscreen)

Tranexamic acid 2.0% by mass Potassium 4-methoxysalicylate 1.0 Compound of the present invention 0.03 Dimethylpolysiloxane 5.0 Decamethylcyclopentasiloxane 25.0 Trimethylsiloxysilicate 5.0 Polyoxyethylene/methylpolysiloxane copolymer 2.0 Dipropylene glycol 5.0 Dextrin palmitate-coated fine-particle zinc oxide (60 nm) 15.0 Dipotassium glycyrrhizinate 0.02 Glutathione 1.0 Thiotaurine 0.05 Sophora flavescens extract 1.0 Paraben q.s. Phenoxyethanol q.s. Trisodium edetate q.s. 2-Ethylhexyl p-methoxycinnamate 7.5 Dimethyldistearylammonium hectorite 0.5 Spherical poly(alkyl acrylate) powder 5.0 Butylethylpropanediol 0.5 Purified water balance Fragrance q.s.

Formulation Example 15 Gel (Whitening)

Potassium 4-methoxysalicylate 0.1% by mass Rucinol 0.3 Dihydrolipoic acid 1.0 Lamium album var. barbatum 0.1 Dimethylpolysiloxane 5.0 Glycerol 2.0 1,3-Butylene glycol 5.0 Polyethylene glycol 1500 3.0 Polyethylene glycol 20000 3.0 Cetyl octanoate 3.0 Citric acid 0.01 Sodium citrate 0.1 Sodium hexametaphosphate 0.1 Compound of the present invention 1.0 Dipotassium glycyrrhizinate 0.1 Ascorbyl glucoside 2.0 Tocopherol acetate 0.1 Scutellaria baicalensis extract 0.1 Saxifraga stolonifera extract 0.1 Trisodium edetate 0.1 Xanthan gum 0.3 Acrylic acid/alkyl methacrylate copolymer 0.05 (Pemulen TR-2) Agar powder 1.5 Phenoxyethanol q.s. Dibutylhydroxytoluene q.s. Purified water balance

Formulation Example 16 Pack (Moisturizing)

Trans-4-aminomethylcyclohexanecarboxylic acid 10.0% by mass methylamide hydrochloride Dihydrolipoamide 1.0 Rosa multiflora fruit extract 0.1 Ethanol 10.0 1,3-Butylene glycol 6.0 Polyethylene glycol 4000 2.0 Olive oil 1.0 Macadamia nut oil 1.0 Phytosteryl hydroxystearate 0.05 Lactic acid 0.05 Sodium lactate 0.1 Disodium L-ascorbyl sulfate 0.1 Compound of the present invention 0.5 Potassium 2-L-Ascorbyl α-tocopheryl phosphate 0.1 Vitamin E acetate 0.1 Fish collagen 0.1 Sodium chondroitin sulfate 0.1 Sodium carboxymethyl cellulose 0.2 Polyvinyl alcohol 12.0 p-Hydroxybenzoate q.s. Purified water balance Fragrance q.s.

Formulation Example 17 Lotion (Moisturizing)

Tranexamic acid 1.0% by mass Potassium 4-methoxysalicylate 1.0 Lipoic acid 10.0 Hamamelis 0.1 Silica-coated zinc oxide 0.1 Hypotaurine 0.1 Sophora flavescens extract 0.1 Peach kernel extract 0.1 Beech sprout extract 0.1 Retinol 0.1 Compound of the present invention 0.01 Ethyl alcohol 5.0 Glycerol 1.0 1,3-Butylene glycol 5.0 Polyoxyethylene polyoxypropylene decyltetradecyl ether 0.2 Sodium hexametaphosphate 0.03 Trimethylglycine 1.0 Sodium polyaspartate 0.1 Potassium 2-L-Ascorbyl α-tocopheryl phosphate 0.1 Thiotaurine 0.1 Green tea extract 0.1 Peppermint extract 0.1 Iris root extract 1.0 Trisodium EDTA 0.1 Carboxyvinyl polymer 0.05 Potassium hydroxide 0.02 Phenoxyethanol q.s. Purified water balance Fragrance q.s. 

1. A whitening agent comprising, as an active ingredient, a heterocyclic compound represented by formula (1) or a pharmacologically acceptable salt thereof:

wherein R₁, R₂, and R₂′ are each independently C₁₋₃ alkyl; Y is S or O; and p is an integer of 0 to 3, wherein when p is 2 or 3, the groups R₁ may be the same or different.
 2. The whitening agent of claim 1, wherein Y is S.
 3. The whitening agent of claim 1, wherein R₂ and R₂′ are methyl.
 4. The whitening agent of claim 1, wherein p is 1 or
 2. 5. The whitening agent of claim 4, wherein R₁ is substituted in at least one of the ortho position and the para position relative to the —NH— group.
 6. The whitening agent of claim 1, wherein the active ingredient inhibits melanin production.
 7. A skin external preparation comprising (a) a dermatologically acceptable carrier or adjuvant and (b) a heterocyclic compound represented by formula (1) or a pharmacologically acceptable salt thereof:

wherein R₁, R₂, and R₂′ are each independently C₁₋₃ alkyl; Y is S or O; and p is an integer of 0 to 3, wherein when p is 2 or 3, the groups R₁ may be the same or different.
 8. The skin external preparation according to claim 7, wherein the preparation is a cosmetic.
 9. A method for inhibiting melanin production comprising topically applying to the skin of a subject in need thereof a preparation comprising an effective amount of a heterocyclic compound represented by formula (1) or a pharmacologically acceptable salt thereof:

wherein R₁, R₂; and R₂′ are each independently C₁₋₃ alkyl; Y is S or O; and p is an integer of 0 to 3, wherein when p is 2 or 3, the groups R₁ may be the same or different.
 10. The method of claim 9, wherein the heterocyclic compound acts as a skin-whitening agent. 